Hypertension affects over 1 billion patients
worldwide. The World Health Organization (WHO)
estimated that poor blood pressure (BP) control is
responsible for 66% of the strokes and 50% of
ischemic heart disease.1 New data from the Fram-
ingham Heart Study suggests that individuals who
are normotensive at age 55 have a 90% lifetime risk
for developing hypertension.2 Even though general
awareness and treatment options for hypertension
have increased, control rates are still inadequate.
For several decades, renin (re' nin) and the
enzymes that catalyze the renin-angiotensin-
aldosterone system (RAAS) have been targets of in-
terest as inhibitors of the RAAS. Inhibition of this
system is a viable therapeutic strategy, not only for
treatment of hypertension, but also for the clinical
benefits that it provides beyond BP reduction, such
as in the management of heart failure ad progressive
kidney disease.3 The RAAS can be manipulated at
several steps including enzyme inhibition reninn and
angiotensin converting enzyme (ACE)] and angio-
tensin II receptor blockade (ARB) (Figure 1). Sev-
eral peptide-like renin inhibitors have been synthe-
sized in the past, but poor pharmacokinetic proper-
ties limited the clinical use of these agents.5 In April
2006, the FDA accepted the new drug application of
aliskiren (a lis' kar in) by Novartis for the treatment
for hypertension both as monotherapy and in co-

administration with other antihypertensive agents.
Aliskiren (Tekturna [tek' tfir na]) was approved by
the FDA on March 6, 2007 for the treatment of hy-
pertension either as monotherapy or in combination
with other agents. This approval marks the first new
class of antihypertensive to be available in over 10
years. This article will evaluate the clinical pharma-
cology, pharmacokinetics and review published
clinical trials on aliskiren.

Clinical pharmacology
Direct renin inhibitors target the renin system
at the point of activation. Aliskiren binds to a pocket
in the renin molecule, blocking angiotensinogen
cleavage. It is a highly specific inhibitor of renin and
has little to no effect on other human enzymes.5 Cur-
rently there are 4 classes of agents that act on the
renin system: ACE-inhibitors, ARBs, beta-blockers
and aldosterone receptor antagonists. However,
ACE-inhibitors and ARBs both activate compensa-
tory feedback mechanisms that result in renin re-
lease. Increased plasma renin activity (PRA) stimu-
lates conversion of angiotensinogen to angiotensin I
(Ang I) with subsequent conversion to angiotensin II
(Ang II) by remaining uninhibited angiotensin con-
verting enzyme (ACE) and ACE independent
rIL U

mm

SPharmaNote

VOLUME 22, ISSUE 6 MARCH 2007

INSIDE THIS ISSUE:

ALISKIREN: A DIRECT RENIN INHIBITOR

'r*

Volume 22, Issue 6 March 2007

PharmaNote

(chymase) pathways. In contrast, renin inhibitors
neutralize any compensatory increase in PRA and
prevent the formation of both Ang I and Ang II.
Kleinhert et al.6 suggested that blood pressure lower-
ing activity of renin inhibitors must be due, in part, to
inhibition of plasma renin activity, but at higher
doses, renin inhibitors might also act via other
mechanisms, such as inhibition of tissue renin.
In healthy volunteers, after oral doses of 40 to
640 mg/day of aliskiren, plasma alikiren concentra-
tion increased with increasing dose, with peak con-
centrations after 3 to 6 hours. The plasma half-life
averaged 23.7 hours (range 20-45 h), allowing once
daily administration. Oral bioavailability of aliskiren
is very low (2.7%) with plasma steady-state concen-
trations reached after 5 to 8 days of treatment. When
aliskiren is taken with food, AUC is reduced by ap-
proximately 62%; whether this is a clinically signifi-

cant reduction is currently unclear. Volume of distri-
bution is < 2 L/kg and the drug is approximately
50% protein bound.7 The main elimination route is
via biliary excretion as unchanged drug. Less than
1% of the oral drug is excreted in the urine. It is not
metabolized by CYP450, does not interfere with the
action of warfarin, and shows no clinically relevant
pharmacokinetic interactions with lovastatin, at-
enolol, celecoxib, or cimetidine. Aliskiren displays
linear pharmacokinetics across a dose range of 75 to
600 mg.8

iskiren 150 mg, 300 mg, or 600 mg or placebo after a
2- to 4-week, single-blind, placebo run-in. The pa-
tients were part of a larger cohort participating in an
8-week trial. A subgroup of 216 patients underwent
24-hour ambulatory blood pressure monitoring at
baseline and at the end of the study. The authors
demonstrated a statistically significant change from
baseline in 24 hour mean ambulatory DBP and SBP
with all 3 doses of aliskiren compared to placebo(p <
0.0001 for all 3 doses of aliskiren)9(Table 1).

ramipril monotherapy. In the ARB combination the 600 mg
study, the addition of 75 or 150 mg of aliskiren to incidence of
150 mg of irbesartan alone, for 3 weeks, resulted in was reduced
significantly lower night-time pressures compared with aliskire
with irbesartan monotherapy. effects note
rized in Tab
Adverse Effects
Aliskiren was well tolerated as either mono- Dosing/Cosi
therapy or in combination therapy with other anti- Alth
hypertensive agents. Discontinuation occurred in 3.5 treatment of
to 5 % of the patients.13 The most common adverse dations and
events included headaches (2.7% 6.1%) and naso- clinical trial
pharyngitis (0.5 5.4%). Diarrhea occurred in a day. No sign
dose-related manner, with the highest incidence at served with

t
tough aliskiren has been approved for the
hypertension, formal dosing recommen-
cost are not available. Doses used in the
s ranged from 37.5 mg to 600 mg once a
lificant blood pressure reduction was ob-
the 37.5 mg daily dose; thus, is not likely

to be used clinically. Also, an aliskiren dose of 600 Summary
mg daily is not associated with additional blood pres- Renin-angiotensin-aldosterone system inhibi-
sure reduction or higher response rates than those tion is a good therapeutic strategy not only for treat-
seen with the 300 mg dose. The FDA approved the ment of hypertension, but also for the clinical bene-
manufacture of 150 mg and 300 mg tablets. fits that it provides beyond BP reduction such as
management of heart failure and progressive kidney
Future studies disease.4 Aliskiren targets renin, the enzyme catalyz-
There are several ongoing studies that are in- ing cleavage of angiotensinogen to angiotensin I
vestigating aliskiren for the prevention of end organ (Ang I), the first and rate-limiting step of the renin-
damage, primary prevention of cardiovascular dis- angiotensin system (RAS). Studies have shown
ease, and prevention of microvascular complications promising data on BP regulation when aliskiren is
in diabetes mellitus. Results from these studies used as monotherapy and in combination with the
might shed more insight into the long-term effects of currently available anti-hypertensives. Further stud-
aliskiren. Some of the ongoing clinical trials are ies will be needed to determine the effects of al-
summarized in Table 4. iskiren on long-term blood pressure regulation and
its ability to protect against end-organ damage.